Dramatic increase in lever pressing activity in rats following cocaine self-administration on high fixed ratio schedules

Abstract

<b>Abstract ID 14745</b> <b>Poster Board 208</b> Cocaine self-administration in rats is a model of cocaine use disorder. The rate of acquisition is highest under fixed ratio (FR) 1 schedule, where every lever press results in a cocaine injection. While FR1 is good for training, it is not considered good for measuring the positive reinforcing effects of cocaine. Progressive ratio (PR) schedules, where the number of lever presses required to get the next cocaine dose gradually increases, are considered a better method for measuring cocaine’s reinforcing efficacy. PR schedules are known to increase the rate of lever pressing activity compared with FR1. Both FR1 and PR schedules of cocaine self-administration follow the compulsion zone theory which states that cocaine induces lever pressing behavior only when cocaine levels are below the satiety threshold and above the priming/remission threshold. We now explore whether cocaine self-administration on FR magnitudes greater than 1 also increases lever pressing activity compared with FR1. Male Sprague Dawley rats (n=8) were trained to self-administer cocaine (i.v.) on an FR1 schedule at different doses. Next, they self-administered cocaine on FR 5, 10, 20 and 50 at a unit dose of 3 μmol/kg until they acquired maintained self-administration at FR50. Standard FR1 sessions were performed before and during FR50 training. Number of lever presses during unloading was lognormally distributed and the geometric mean was calculated. The number of unloading lever presses increased approximately sevenfold from pre-FR50 FR1 sessions (23) to during-FR50 FR1 sessions (158) and increased about elevenfold from pre-FR50 FR1 sessions to FR50 sessions (245). The number of unloading lever presses in FR50 sessions were approximately 1.5-fold higher than during-FR50 FR1 sessions. After completion of FR50 sessions, the standard FR1 sessions were performed on 5 rats twice a week for 4-7 weeks. The number of lever presses significantly decreased from FR50 sessions and reduced by 75% in post-FR50 FR1 sessions (59). However, number of lever presses remained 2.5 times higher in post-FR50 FR1 sessions compared to pre-FR50 FR1 sessions and lever pressing activity did not return to baseline. Despite the differences in number of lever presses, there was no significant difference in the duration of unloading lever pressing activity between all sessions. Inter-press intervals (IPI) were lognormally distributed, and shifted from bimodal to unimodal after exposure to FR50. The number of long IPIs decreased and the number of short IPIs substantially increased resulting in the dramatic increase in lever presses. The increase in rate of unloading lever pressing activity following high FR training may account for reports that cocaine is a positive reinforcer. However, the satiety and remission thresholds, the calculated cocaine level at the first and last unloading lever press, respectively, were similar in all sessions. This confirms that the compulsion zone is not altered after exposure to high FR magnitude and the dramatic increase in the frequency of lever presses improves the resolution of these calculated threshold values. Supported by NIDA grant U01DA050330 (to ABN)